Praziquantel is a synthesized pyrazine isoquinoline derivative, also called cyclo-praziquantel, and is a white or off-white crystalline powder and bitter in taste. It is worldwide recognized as a highly effective and broad-spectrum anti-parasitic drug, and is widely used for treating diseases such as schistosomiasis japonica, schistosomiasis haematobium, schistosomiasis mansoni, clonorchiasis, paragonimiasis, sparganosis mansoni, fasciolopsis, echinococcosis, taeniasis, cysticercosis, etc. It has advantages such as broad spectrum, high efficacy, low toxicity, short therapeutic course and easy to use, etc. In addition to human use, it is also widely used as an anti-parasitic treatment in animals including poultry and livestock. The invention of praziquantel is a major breakthrough in the history of anti-parasitic chemotherapy. In the past 30 years, praziquantel has been the choice of drug for treating various parasitic diseases on the market.
Praziquantel is a racemic mixture composed of (R)-praziquantel and (S)-praziquantel. Scientists have separated and obtained both pure optic isomers of (R)-praziquantel and (S)-praziquantel from synthesized praziquantel, and found in preclinical studies and preliminary clinical trials that: (R)-praziquantel is the active parasiticidal component of praziquantel, while the (S)-praziquantel is inactive or even harmful; at the same dosage, the clinical efficacy of (R)-praziquantel is better than that of praziquantel, where (S)-praziquantel is almost inactive, bitter taste and the major source of side effects. (R)-praziquantel shows lower cardiac toxicity than (S)-praziquantel. Therefore, the development of (R)-praziquantel has substantial clinical values of higher efficacy, less side effects, and better medical compliance, and is highly expected by the World Health Organization for global anti-parasitic chemotherapy. However, the difficult technical problem of low synthetic yield of (R)-praziquantel has been unsolved for many years.
Praziquantel was firstly synthesized in 1975 by Seubert et al, and two pharmaceutical companies in Germany, E. Merck and Bayer AG, have successfully developed this drug, which was the first to appear in the market in the trade name of Cesol in 1980 and now is widely used around the world. The manufacture process of praziquantel has used some toxic and harmful chemicals, such as potassium cyanide, heavy metals, etc., and it has a lengthy route, and rigorous reaction conditions such as high temperature, high pressure. Also, this type of reaction process is difficult to control, and may cause severe pollution.
At present, there are two main approaches for the synthesis of (R)-praziquantel:
1. Chemical resolution: using racemic intermediates or racemic praziquantel as raw material, (R)-praziquantel is synthesized through chemical resolution (Resolution of Praziquantel, Matthew H. Toddl, Australia, PLOS, Neglected Tropical Diseases, September 2011, Volume 5, Issue 9, e1260). In addition to the potential environmental disadvantages of the synthesis of praziquantel, the yield and optical purity of obtained (R)-praziquantel require to be improved, and (S)-praziquantel amine after resolution needs to be recycled and racemized for reuse, which consumes more energy and time.
2. Enzymatic resolution as reported in CN 102911979 A: it needs to racemize dextroisomer, and has a cumbersome process and an overall yield to be improved.